Carvedilol

ABSTRACT

This invention relates to an improved process of preparing carvedilol, as well as a new crystalline hydrate and solvate and forms of carvedilol, processes for the manufacture thereof, and pharmaceutical compositions thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application Ser. No.09/894,798 filed Jun. 28, 2001, now U.S. Pat. No. 6,699,997 and claimsthe benefit of U.S. provisional application Ser. No. 60/349,310, filedJan. 15, 2002, which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to an improved process of preparing carvedilol,as well as a new crystalline hydrate and solvate and forms ofcarvedilol, processes for the manufacture thereof, and pharmaceuticalcompositions thereof.

BACKGROUND OF THE INVENTION

Carvedilol is a nonselective β-adrenergic blocking agent with α₁blocking activity. Carvedilol, also known as (±)1-(9H-carbazol-4-yloxy)-3-[[2(2-methoxyphenoxy)ethyl]amino]-2-propanol,(CAS Registry No. 72956-09-3) has the structure of formula I.

Carvedilol has a chiral center and can exist either as individualstereoisomers or in racemic form. Racemic carvedilol is the activeingredient of COREG®, which is indicated for the treatment of congestiveheart failure and hypertension. The nonselective β-adrenergic activityof carvedilol is present in the S(−) enantiomer and the a, blockingactivity is present in both the R(+) and S(−) enantiomers at equalpotency. Both the racemate and stereoisomers may be obtained accordingto procedures well known in the art (EP B 0127 099).

Synthesis of Carvedilol

U.S. Pat. No. 4,503,067, which is incorporated herein by reference,discloses a process of preparing carvedilol by the following reaction:

in which 4-(oxiran-2-ylmethoxy)-9H-carbazole (formula II) is reactedwith (2-(2-methoxyphenoxy)ethylamine (formula III) to form carvedilol(I). The above process produces a low yield of carvedilol at least inpart because in addition to carvedilol, the process leads to theproduction of a bis impurity of the following structure (formula IV):

(See EP 918055.)

In order to reduce the formation of the formula IV and to increase theyield of carvedilol, EP 918055 discloses using a benzyl protected formof the 2-(2-methoxyphenoxy)ethylamine (III).

Carvedilol Polymorphs

International application No. WO 99/05105, incorporated herein byreference, discloses that carvedilol can be isolated as two polymorphicforms, depending on the method of preparation. The two polymorphicforms, designated Form I and Form II, are reported to be monotropic andare distinguishable by their infrared, Raman and X-ray powderdiffraction spectra. No evidence is found in the literature about theexistence of hydrated solvate states of carvedilol.

Polymorphism is the property of some molecules and molecular complexesto assume more than one crystalline form in the solid state. A singlemolecule may give rise to a variety of crystal forms (also called“polymorphs,” “hydrates,” or “solvates”) having distinct physicalproperties. For a general review of polymorphs and the pharmaceuticalapplications of polymorphs see Pharm Manuf., 3, 33 (1986); J. K.Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K.Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which areincorporated herein by reference.

The existence and physical properties of different crystal forms can bedetermined by a variety of techniques such as X-ray diffractionspectroscopy, differential scanning calorimetry and infraredspectroscopy. Differences in the physical properties of differentcrystal forms result from the orientation and intermolecularinteractions of adjacent molecules (complexes) in the bulk solid.Accordingly, polymorphs, hydrates and solvates are distinct solidssharing the same molecular formula yet having distinct advantageousand/or disadvantageous physical properties compared to other forms inthe polymorph family. The existence and physical properties ofpolymorphs, hydrates and solvates is unpredictable.

One of the most important physical properties of a pharmaceuticalcompound which can form polymorphs, hydrates or solvates, is itssolubility in aqueous solution, particularly the solubility in gastricjuices of a patient. Other important properties relate to the ease ofprocessing the form into pharmaceutical dosages, such as the tendency ofa powdered or granulated form to flow and the surface properties thatdetermine whether crystals of the form will adhere to each other whencompacted into a tablet.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing carvedilolcomprising a step of reacting a compound of formula II,4-(oxiran-2-ylmethoxy)-9H-carbazole,

with a compound of formula III, 2-(2-methoxyphenoxy)ethylamine

wherein the compound of formula III is at a molar excess over thecompound of formula II.

The present invention further provides crystalline carvedilol hydrate.

The present invention further provides crystalline carvedilol.

The present invention further provides crystalline carvedilol(methyl-ethyl-ketone) solvate.

The present invention further provides crystalline carvedilol Form IIIcharacterized by an X-ray powder diffraction pattern having peaks atabout 8.4±0.2, 17.4±0.2, and 22.0±0.2 degrees two-theta.

The present invention further provides crystalline carvedilol Form IVcharacterized by an X-ray powder diffraction pattern having peaks atabout 11.9±0.2, 14.2±0.2, 18.3±0.2, 19.2±0.2, 21.7±0.2, and 24.2±0.2degrees two-theta.

The present invention further provides crystalline carvedilol(methyl-ethyl-ketone) solvate Form V characterized by an X-ray powderdiffraction pattern having peaks at about 4.1±0.2, 10.3±0.2, and10.7±0.2 degrees two-theta.

The present invention further provides carvedilol HCl Hydratecharacterized by an X-ray powder diffraction pattern having peaks atabout 6.5±0.2, 10.2±0.2, 10.4±0.2, 15.8±0.2,16.4±0.2 and 22.2±0.2degrees two-theta.

The present invention further provides a method for preparingcrystalline carvedilol Form I, comprising the steps of dissolvingcarvedilol in a solution by heating; heating the solution until thecrystalline carvedilol is completely dissolved; reducing the temperatureof the solution; agitating the solution for a period of time; furtherreducing the temperature of the solution; further agitating the solutionfor a period of time; and collecting crystalline carvedilol Form I.

The present invention further provides a method for preparingcrystalline carvedilol Form II, comprising the steps of forming asolution of carvedilol by dissolving carvedilol in a solvent;precipitating carvedilol Form II by cooling the solution; and, isolatingcrystalline carvedilol Form II.

The present invention further provides a method for preparingcrystalline carvedilol Form II, comprising the steps of forming asolution of carvedilol by dissolving carvedilol in a solvent mixture;precipitating carvedilol Form II by cooling the solution to about −20°C.; and, isolating crystalline carvedilol Form II.

The present invention further provides a method for preparingcrystalline carvedilol Form III, comprising the steps of dissolvingcarvedilol in a solvent to form a solvent solution; and, precipitatingcrystalline carvedilol Form III from the solvent solution using water asan anti-solvent.

The present invention further provides a method for preparingcrystalline carvedilol Form III, comprising the steps of dissolvingcarvedilol in a solution by heating; cooling the solution mixture; and,collecting crystalline carvedilol Form III.

The present invention further provides a method for preparingcrystalline carvedilol Form IV, comprising the steps of dissolvingcarvedilol in a solvent to form a solvent solution; adding ananti-solvent to the solvent solution; and, precipitating crystallinecarvedilol Form IV from the solvent solution.

The present invention further provides a method for preparingcrystalline carvedilol Form V, comprising the steps of dissolvingcarvedilol in a solvent to form a solvent solution; and, precipitatingand isolating crystalline carvedilol Form V from the solvent solution.

The present invention further provides a method for preparingcrystalline carvedilol Form V, comprising the steps of dissolvingcarvedilol in a solvent to form a solvent solution; and, precipitatingand isolating crystalline carvedilol Form V from the solvent solutionwherein the precipitation step is performed by adding an anti-solvent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. shows the X-ray diffraction pattern of carvedilol Form III.

FIG. 2. shows the DTG thermal profile of carvedilol Form III.

FIG. 3. shows the X-ray diffraction pattern of carvedilol Form IV.

FIG. 4. shows the DTG thermal profile of carvedilol Form IV.

FIG. 5. shows the X-ray diffraction pattern of carvedilol Form V.

FIG. 6. shows the DTG thermal profile of carvedilol Form V.

FIG. 7. shows the X-ray diffraction pattern of carvedilol HCl.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “carvedilol” includes hydrates and solvates ofcarvedilol. The term “water content” refers to the content of water,based upon the Loss on Drying method (the “LOD” method) as described inPharmacopeia Forum, Vol. 24, No. 1, p. 5438 (January-February 1998), theKarl Fisher assay for determining water content or thermogravimetricanalysis (TGA). The term “equivalents of water” means molar equivalentsof water. All percentages herein are by weight unless otherwiseindicated. Those skilled in the art will also understand that the term“anhydrous”, when used in reference to carvedilol, describes carvedilolwhich is substantially free of water. One skilled in the art willappreciate that the term “hemihydrate”, when used in reference tocarvedilol, describes a crystalline material having a water content ofabout 2.2% w/w. One skilled in the art will appreciate that the term“hydrate”,in reference to carvedilol hydrochloride a crystallinematerial having a water content of about or above 2% w/w. One skilled inthe art will also appreciate that the term “solvate ofmethyl-ethyl-ketone” refers to carvedilol in which solvent is containedwithin the crystal lattice in quantities above 1%. One skilled in theart will also appreciate that the term “solvate of methyl-ethyl-ketone”which contains one mole of is characterized by a methyl-ethyl-ketonecontent of about 14% by weight.

Hydrate and solvate forms of carvedilol are novel and distinct from eachother in terms of their characteristic powder X-ray diffraction patternsand their thermal profiles.

For the purposes of this specification, ambient temperature is fromabout 20° C. to about 25° C.

All powder X-ray diffraction patterns were obtained by methods known inthe art using a Philips X-ray powder diffractometer. Copper radiation ofλ=1.5418 Å was used.

Measurement of thermal analysis are conducted for the purpose ofevaluating the physical and chemical changes that may take place in aheated sample. Thermal reactions can be endothermic (e.g., melting,boiling, sublimation, vaporization, desolvation, solid-solid phasetransitions, chemical degradation, etc.) or exothermic (e.g.,crystallization, oxidative decomposition, etc.) in nature. Suchmethodology has gained widespread use in the pharmaceutical industry incharacterization of polymorphism. Thermal measurements have proven to beuseful in the characterization of polymorphic systems. The most commonlyapplied techniques are thermogravimetry (TGA), differential thermalanalysis (DTA), and differential scanning calorimetry (DSC).

The DTA and TGA curves presented herein were obtained by methods knownin the art using a DTG Shimadzu model DTG-50 (combined TGA and DTA). Theweight of the samples was about 9 to about 13 mg. The samples werescanned up to about 300° C. or above at a rate of 10° C./min. Sampleswere purged with nitrogen gas at a flow rate of 20 ml/min. Standardalumina crucibles covered lids with one hole.

Thermogravimetry analysis (TGA) is a measure of the thermally inducedweight loss of a material as a function of the applied temperature. TGAis restricted to transitions that involve either a gain or a loss ofmass, and it is most commonly used to study desolvation processes andcompound decomposition.

Karl Fisher analysis, which is well known in the art, is also used todetermine the quantity of water in a sample.

As used herein, a solvent is any liquid substance capable of dissolvingcarvedilol. As used herein, the term “anti-solvent” means a liquid inwhich a compound is poorly soluble. The addition of an anti-solvent to asolvent reduces the solubility of a compound. As used herein a mixtureof solvents refers to a composition comprising more than one solvent.

As used herein, the term “neat” conditions refers to conditions of areaction wherein the solvent of the reaction is one of the reactants.

Synthesis of Carvedilol

According to one embodiment, the present invention is a process forpreparing carvedilol comprising a step of reacting a compound of formulaII, 4-(oxiran-2-ylmethoxy)-9H-carbazole,

with a compound of formula III, 2-(2-methoxyphenoxy)ethylamine

The new procedure results in a higher yield of carvedilol than has beenreported in the prior art. In addition, the product of the new procedureis nearly free of bis impurities and the reaction is more rapid.

Preferably, the compound of formula III is at a molar excess over thecompound of formula II. The compound of formula III and the compound offormula II are preferably at a molar ratio from about 1.5:1 to about100:1. More preferably, the compound of formula III and the compound offormula II are at a molar ration from about 2.8:1 to about 10:1. Mostpreferably, the compound of formula III and the compound of formula IIare at a molar ratio from about 2.8:1 to about 6:1.

In one embodiment of the present invention, the reacting step isperformed in a solvent. The solvent is preferably selected from thegroup consisting of toluene, xylene and heptane. In an alternativeembodiment, the reacting step is performed in a solvent mixture whereinthe solvent mixture comprises multiple solvents. Preferably, a solventof the solvent mixture is selected from the group consisting of toluene,xylene and heptane.

The reacting step is preferably performed at a temperature from about25° C. and about 150° C. Most preferably, the reacting step is performedat a temperature from about 60° C. and about 120° C.

In an alternative embodiment, the reacting step is performed under neatconditions. The neat conditions may obtained by melting a solid form ofthe compound of formula III to form a liquid and, dissolving thecompound of formula II in the liquid to form a reaction mixture.

The reaction performed under neat conditions may further comprise a stepof reducing the temperature of the reaction mixture after dissolving thecompound of formula II. The temperature is preferably reduced to about70° C.

The reaction performed under neat conditions may further comprise a stepof adding an organic solvent: water mixture to the reaction mixture. Theorganic solvent is preferably selected from the group consisting ofethyl acetate, methyl isobutyl ketone, methyl ethyl ketone and butylacetate.

The reaction performed under neat conditions may further comprise a stepof adjusting the pH of the organic solvent: water mixture after it isadded to the reaction mixture. The pH is preferably adjusted to lessthan about pH 5. More preferably, the pH is adjusted from about pH 3 toabout pH 5.

Optionally, the process further comprises the steps of isolatingcarvedilol hydrochloride after adjusting the pH, and purifyingcarvedilol.

Carvedilol hydrochloride is optionally isolated as a hydrate. CarvedilolHCl isolated as a hydrate typically has an XRD peaks are found at about6.5±0.2, 10.2±0.2, 10.4±0.2, 14.2±0.2, 14.7±0.2, 16.4±0.2, 17.7±0.2,20.0±0.2, 21.9±0.2, 25.2±0.2 degrees to 2-theta.

The reaction preformed under neat conditions may further comprise stepsof, isolating carvedilol from the reaction mixture after adjusting thepH, and purifying carvedilol. Optionally, carvedilol may be purified bymethods well known in the art. (See EP B 0127 099.)

Novel Methods for Preparing Crystalline Carvedilol Form I and Form II

One aspect of the present invention provides a method for preparingcrystalline carvedilol Form I, by dissolving carvedilol in a solventuntil the crystalline carvedilol is completely dissolved, reducing thetemperature of the solution and agitating the solution for a period oftime, further reducing the temperature of the solution and agitating thesolution for a period of time and, collecting crystalline carvedilolForm I.

The dissolving step is optionally performed by heating the solvent.

The dissolving step is optionally performed by heating crystallinecarvedilol at a temperature from about 50° C. to about 60° C. for about6 hours.

The dissolving step is optionally performed by suspending thecrystalline carvedilol in ethyl acetate.

The dissolving step is optionally performed by heating the solution toabout 77° C.

The step of reducing the temperature of the solution is optionallyperformed by cooling the solution to about 50° C. in a time period of 15min.

The step of agitating solution is optionally performed at about 50° C.for about 48 hours.

The step of further reducing the temperature of the solution isoptionally performed by cooling the solution to about 10° C. in about0.75 hours with agitation.

The step of further agitating the solution is optionally performed bystirring the suspension for more than 5 hours. The step of furtheragitation may optionally be performed by stirring the suspension forabout 24 hours.

The drying step may be performed by heating crystalline carvedilol at atemperature from about 50° C. to about 60° C. for about 6 hours.

The suspending step may be performed by suspending the crystallinecarvedilol in ethyl acetate.

The heating step may be performed by heating the solution to about 77°C.

Another aspect of the present invention provides a method for preparingcrystalline carvedilol Form II, comprising the steps of forming asolution of carvedilol by dissolving carvedilol in a solvent,precipitating carvedilol Form II by cooling the solution, and isolatingcrystalline carvedilol Form II.

Optionally, the step of dissolving carvedilol is performed at atemperature from about 40° C. to about the boiling temp of the solvent.

Optionally, the step of cooling the solution is performed by reducingthe temperature from about −20° C. to about ambient temperature.

Optionally, the solvent is selected from the group consisting ofmethanol, absolute ethanol, 1-propanol, isopropanol, n-butanol, ethyleneglycol, butyl acetate, isobutyl methyl ketone, dichloromethane,dichloroethane, acetonitrile, acetone, isoamylalcohol, xylene andtoluene.

Optionally, the precipitated carvedilol Form II is isolated byfiltration.

Another aspect of the present invention provides a method for preparingcrystalline carvedilol Form II, comprising the steps of: forming asolution of carvedilol by dissolving carvedilol in a solvent mixture,precipitating carvedilol Form II by cooling the solution to about −20°C., and isolating crystalline carvedilol Form II.

Optionally, the carvedilol is dissolved in a solution at a temperaturefrom about 40° C. to about the boiling temperature of the solvent.

Optionally, the carvedilol Form II is isolated by filtration.

Optionally, the step of cooling the reaction is performed by cooling thesolution to a temperature from about −20° C. to ambient temperature.

Optionally, the solvent mixture is selected from the group consisting ofacetone:cyclohexane, chloroform:cyclohexane, dichloroethane:cyclohexane,dichloromethane:cyclohexane, pyridine:cyclohexane,tetrahydrofuran:cyclohexane, dioxane:cyclohexane, acetone:hexane,chloroform:hexane, dichloroethane:hexane, dichloromethane:hexane,tetrahydrofuran:hexane and ethanol:hexane.

Novel Carvedilol Polymorphs

In another aspect the present invention provides new crystalline formsof carvedilol, designated Forms III, IV, V and processes for themanufacture thereof. Moreover, the present invention provides a newhydrate form of carvedilol, having water content of about 2% by weightand processes for their manufacture. In another embodiment, the presentinvention provides new solvate forms of carvedilol, having solventcontent up to about 14% by weight, wherein the solvent is methyl ethylketone, and processes for their manufacture. These hydrate/solvate formsof carvedilol are useful as intermediates for the synthesis ofcarvedilol drug substances.

Procedures for Crystallizing Novel Forms of Carvedilol

The novel hydrates/solvates forms provided herein are optionally formedby precipitating carvedilol as a crystalline solid from a solvent or asolvent mixture. It will be understood by those of skill in the art,that other methods may also be used to form the hydrate/solvates formdisclosed herein. Alternatively the polymorphs may be formed by routinemodification of the procedures disclosed herein.

Formation of Crystalline Carvedilol Form III

One embodiment of the present invention provides a method for preparingcrystalline carvedilol Form III, which comprises the steps of forming asolvent solution containing carvedilol; and, precipitating crystallinecarvedilol Form III from the solvent solution using water as ananti-solvent. The invention provides for a dissolving step wherein wateris present in the solvent solution during the dissolving step. Theinvention also provides for a precipitation step wherein water is addedto the solution after carvedilol is fully dissolved in a solvent.

Optionally, to form the solvent solution containing carvedilol,carvedilol may be dissolved in a solvent at elevated temperature. Thepreferred elevated temperature is from about 40 to about 90° C. Mostpreferably the elevated temperature is about 55° C. Alternatively,carvedilol may be dissolved in a solvent at ambient temperature.

Another embodiment of the present invention provides, forming thesolvent solution containing carvedilol, by dissolving carvedilol in asolvent and inducing precipitation of crystalline carvedilol Form III bythe addition of an anti-solvent. Solvents are optionally selected fromthe group which includes pyridine, dioxane, isopropanol and chloroform.Anti-solvents are optionally selected from the group which includeswater and hexane.

An alternative embodiment of the present invention provides, forming thesolvent solution containing carvedilol by dissolving carvedilol in anorganic solvent and water and precipitating crystalline carvedilol FormIII. In this embodiment the organic solvent is optionally an alcohol.The alcohol is preferably selected from the group consisting of methanoland ethanol. Alternatively, the organic solvent may be selected from thegroup of solvents consisting of pyridine, dioxane, and ethyl acetate andtetrahydrofuran.

An alternative embodiment of the present invention provides, a methodfor preparing crystalline carvedilol Form III, comprising the steps of:drying crystalline carvedilol at elevated temperature, suspendingcrystalline carvedilol in a solution mixture, heating the solutionmixture until the crystalline carvedilol is completely dissolved,cooling the solution mixture, and collecting crystalline carvedilol FormIII.

Optionally, the drying step may be performed by heating crystallinecarvedilol at a temperature from about 50° C. to about 60° C. for about6 hours.

Optionally, the suspending step may be performed by suspending thecrystalline carvedilol in a solution mixture of ethyl acetate: water(150:40).

Optionally, the heating step may be performed by heating the solutionmixture from about 60 to about 70° C. with agitation until thecrystalline carvedilol is completely dissolved.

Optionally, the cooling step may be performed by cooling the solutionmixture to about to 10° C. for a period of about 3 hours with agitation.

Formation of Crystalline Carvedilol Form IV

The present invention also provides a method for preparing crystallinecarvedilol Form IV by forming a solvent solution containing carvediloland inducing precipitation of crystalline carvedilol Form IV by theaddition of an “anti-solvent”. In this embodiment, solvents areoptionally selected from the group which includes methyl ethyl ketone,and methyl isobutyl ketone. Anti-solvents are optionally selected fromthe group which includes cylcohexane and heptane.

Optionally, to form crystalline carvedilol Form IV carvedilol may bedissolved in a solvent at from below ambient temperature to elevatedtemperatures. The preferred temperature is from about 10° to about 50°C. Most preferably the temperature is ambient temperature.

Formation of Crystalline Carvedilol Form V

The present invention also provides a method for preparing crystallinecarvedilol Form V by forming a solvent solution containing carvediloland inducing precipitation of crystalline carvedilol solvate Form V bycooling or by adding an anti-solvent. In this embodiment, the solvent isoptionally selected from the group which includes methyl ethyl ketone.Anti-solvents are optionally selected from the group which includescylcohexane and hexane.

Optionally, to form crystalline carvedilol Form V the carvedilol may bedissolved in a solvent solution at elevated temperature. The preferredelevated temperature is from about 10 to about 80° C. Most preferablythe elevated temperature is about 55° C. Alternatively, carvedilol maybe dissolved in a solvent solution at ambient temperature.

Novel Hydrate and Solvate Crystal Forms of Carvedilol

The present invention provides novel crystal forms of carvedilol whichwill be designated as Forms III, IV and V, as well as carvedilol HCl.These forms can be distinguished from the prior art forms of carvediloland from each other by characteristic powder X-ray diffraction patternsand thermal profiles.

The different crystal forms may also be characterized by theirrespective solvation state. The most commonly encountered solvates amongpharmaceuticals are those of 1:1 stoichiometry. Occasionally mixedsolvate species are encountered. When water or solvent is incorporatedinto the crystal lattice of a compound in stoichiometric proportions,the molecular adduct or adducts formed are referred to as hydrates orsolvates.

Crystalline Carvedilol Form III

Carvedilol Form III (“Form III”) is characterized by an X-raydiffraction pattern with peaks at about 8.4±0.2, 9.3±0.2, 11.6±0.2,13.2±0.2, 13.5±0.2, 14.2±0.2, 15.3±0.2, 15.8±0.2,17.4±0.2, 18.4±0.2,19.4±0.2, 20.6±0.2, 21.4±0.2, 22.0±0.2, 26.5±0.2 and 27.6±0.2 degreestwo-theta. The most characteristic peaks of Form III are at about8.4±0.2, 17.4±0.2, and 22.0±0.2 degrees two-theta. The diffractionpattern is reproduced in FIG. 1.

The DTG thermal profile of Form IV is shown in FIG. 2. The differentialscanning calorimetry (DSC) thermal profile of Form III shows one meltingpeak around 100° C. (96° C.-110° C.), depending on the samples and onthe particle size. This melting peak is concomitant to a loss on dryingof about 2% as measured by thermal gravimetric analysis (TGA). Theamount of water in the sample as determined by Karl Fisher analysis isin good agreement with the value obtained from TGA, thus confirming thatthe loss on drying is due to the dehydration of water, and indicatingthat this material is a hemihydrate.

Crystalline Carvedilol Form IV

Carvedilol Form IV (“Form IV”) is characterized by an X-ray diffractionpattern with peaks at about 11.9±0.2, 14.2±0.2, 15.7±0.2, 16.5±0.2,17.7±0.2, 18.3±0.2, 19.2±0.2, 19.6±0.2, 21.7±0.2, 22.2±0.2, 23.9±0.2,24.2±0.2, 24.9±0.2, 27.4±0.2 and 28.2±0.2 degrees two-theta. The mostcharacteristic peaks of Form IV are at about 11.9±0.2, 14.2±0.2,18.3±0.2, 19.2±0.2, 21.7±0.2, and 24.2±0.2 degrees two-theta. Thediffraction pattern is reproduced in FIG. 3.

The DTG thermal profile of Form IV is shown in FIG. 4. The DSC thermalprofile of Form IV shows one melting peak at about 104° C.

Crystalline Carvedilol Form V

Carvedilol Form V (“Form V”) is characterized by an X-ray diffractionpattern with peaks at about 4.1±0.2, 10.3±0.2, 10.7±0.2, 11.5±0.2,12.6±0.2, 14.0±0.2, 14.8±0.2, 15.4±0.2, 16.4±0.2, 16.8±0.2, 18.8±0.2,20.8±0.2, 21.1±0.2, 21.6±0.2, and 25.4±0.2, degrees two-theta. The mostcharacteristic peaks of Form IV are at about 4.1±0.2, 10.3±0.2, 10.7±0.2and 11.5±0.2 degrees two-theta. The diffraction pattern is reproduced inFIG. 5.

The DTG thermal profile of Form V is shown in FIG. 6. The DSC thermalprofile of Form V shows a solvent desorption endotherm at about 67° C.,followed by a recrystallization event, and a melting peak at 115° C. Thedesorption endotherm is concomitant to a loss on drying of about 14% asdetermined by TGA. This behavior is consistent with the loss of amolecule of MEK per molecule of carvedilol (the calculatedstoichiometric value of mono-MEK is 15%).

Carvedilol HCl Hydrate

Crystalline Carvedilol HCl is characterized by an X-ray diffractionpattern with peaks at about 6.5±0.2, 10.2±0.2, 10.4±0.2, 14.2±0.2,14.7±0.2, 15.8±0.2, 16.4±0.2, 17.7±0.2, 20.0±0.2, 21.5±0.2, 21.9±0.2,22.2±0.2, 22.9±0.2,25.2±0.2, 25.3±0.2, 27.2±0.2, 27.4±0.2, 28.2±0.2,28.6±0.2, 29.6±0.2 degrees two theta. The most characteristic peaks ofcrystalline carvedilol HCl are at about 6.5±0.2, 10.2±0.2, 10.4±0.2,15.8±0.2,16.4±0.2 and 22.2±0.2 degrees two-theta. The diffractionpattern is reproduced in FIG. 7.

The DTG thermal profile of carvedilol HCl shows two endothermic peaks. Apeak at 118° C. is a dehydration peak. A second peak endothermic peak at135° C. is due to melting of the sample. LOD for this sample is 3.5%.The Water content of this sample as measured by Karl-Fisher analysis is3.7%. Thus the Karl-Fisher analysis is in agreement with LOD value, andconfirm the presence of hydrate in this sample. The expected value forcarvedilol HCl monohydrate is 3.9%

A Pharmaceutical Composition Containing Carvedilol

According to another aspect, the present invention relates to apharmaceutical composition comprising one or more of the novel crystalforms of carvedilol disclosed herein and at least one pharmaceuticallyacceptable excipient. Such pharmaceutical compositions may beadministered to a mammalian patient in a dosage form.

The dosage forms may contain one or more of the novel forms ofcarvedilol or, alternatively, may contain one or more of the novel formsof carvedilol as part of a composition. Whether administered in pureform or in a composition, the carvedilol form(s) may be in the form of apowder, granules, aggregates or any other solid form. The compositionsof the present invention include compositions for tableting. Tabletingcompositions may have few or many components depending upon thetableting method used, the release rate desired and other factors. Forexample, compositions of the present invention may contain diluents suchas cellulose-derived materials like powdered cellulose, microcrystallinecellulose, microfine cellulose, methyl cellulose, ethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose salts and other substituted andunsubstituted celluloses; starch; pregelatinized starch; inorganicdiluents such calcium carbonate and calcium diphosphate and otherdiluents known to one of ordinary skill in the art. Yet other suitablediluents include waxes, sugars (e.g. lactose) and sugar alcohols likemannitol and sorbitol, acrylate polymers and copolymers, as well aspectin, dextrin and gelatin.

Other excipients contemplated by the present invention include binders,such as acacia gum, pregelatinized starch, sodium alginate, glucose andother binders used in wet and dry granulation and direct compressiontableting processes; disintegrants such as sodium starch glycolate,crospovidone, low-substituted hydroxypropyl cellulose and others;lubricants like magnesium and calcium stearate and sodium stearylfumarate; flavorings; sweeteners; preservatives; pharmaceuticallyacceptable dyes and glidants such as silicon dioxide.

Dosage forms may be adapted for administration to the patient by oral,buccal, parenteral, ophthalmic, rectal and transdermal routes. Oraldosage forms include tablets, pills, capsules, troches, sachets,suspensions, powders, lozenges, elixirs and the like. The novel forms ofcarvedilol disclosed herein also may be administered as suppositories,ophthalmic ointments and suspensions, and parenteral suspensions, whichare administered by other routes. The most preferred route ofadministration of the carvedilol forms of the present invention is oral.

Capsule dosages will contain the solid composition within a capsulewhich may be coated with gelatin. Tablets and powders may also be coatedwith an enteric coating. The enteric-coated powder forms may havecoatings comprising phthalic acid cellulose acetate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate,carboxymethylethylcellulose, a copolymer of styrene and maleic acid, acopolymer of methacrylic acid and methyl methacrylate, and likematerials, and if desired, they may be employed with suitableplasticizers and/or extending agents. A coated tablet may have a coatingon the surface of the tablet or may be a tablet comprising a powder orgranules with an enteric-coating.

The currently marketed form of carvedilol is available as a 3.125 mg, a6.25 mg, a 12.5 mg, and a 25 mg tablet which includes the followinginactive ingredients: colloidal silicon dioxide, crospovidone,hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethyleneglycol, polysorbate 80, povidone, sucrose, and titanium dioxide.

The function and advantage of these and other embodiments of the presentinvention will be more fully understood from the examples below. Thefollowing examples are intended to illustrate the benefits of thepresent invention, but do not exemplify the full scope of the invention.

EXAMPLES Example 1 Preparation of Carvedilol in Neat Conditions

2-(2-Methoxyphenoxy)ethylamine (III) (4.89 g) was heated to about 100°C., after which 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) (3.31 g) wasadded portionwise. After approximately 20 minutes, the reaction mixturewas cooled to about 70° C., after which water (25 ml) and ethyl acetate(15 ml) were added. The pH of the two-phase mixture was then adjusted to5 with 2 N hydrochloric acid. The solid that formed, Carvedilolhydrochloride hydrate, is filtered, washed with water (20 ml) followedwith ethylacetate (15 ml).

The resulting material is reslurried in ethylacetate (50 mL) and water(20 mL) containing 5% sodium carbonate until the pH reached 7.5. Theorganic phase was separated and dried over sodium sulfate. The driedsolution was concentrated to a turbid solution and cooled overnight toabout 4° C. Precipitated carvedilol was isolated by filtration andcrystallized from isopropanol.

Example 2 Preparation of Carvedilol in Neat Conditions

2-(2-Methoxyphenoxy)ethylamine (III) (4.89 g) was heated to about 100°C., after which 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) (3.31 g) wasadded portionwise. After approximately 20 minutes, the reaction mixturewas cooled to about 70° C., after which water (25 ml) and ethyl acetate(15 ml) were added. The pH of the two-phase mixture was then adjusted to5 with 2 N hydrochloric acid. The solid that formed, Carvedilolhydrochloride hydrate, is filtered, washed with water (20 ml) followedwith ethylacetate (15 ml).

The resulting material is reslurried in ethyl acetate (50 mL) and water(20 mL) containing 5% sodium carbonate until the pH reached 7.5. Theorganic phase was separated and dried over sodium sulfate. The driedsolution was concentrated to a turbid solution and cooled overnight toabout 4° C. Precipitated carvedilol was isolated by filtration andcrystallized from methanol.

Example 3 Process for Preparing Form I of Carvedilol

The dried crystalline carvedilol (220 g carvedilol) is dissolved in 2200mL ethyl acetate. The ethyl acetate solution is heated with agitation to77° C. until the solid is completely dissolved. The ethyl acetatesolution was then cooled with agitation to about 50° C. in a time periodof 15 minutes. The cooled solution was stirred for 48 hours. Thesolution was then cooled to 10° C. in 0.75 hours with agitation. Afterstirring the suspension for additional 24 hours, the product wasfiltered. Pure Crystalline carvedilol Form I (170 g) was obtained.

Example 4 Preparation of Crystalline Carvedilol Form II

Crystalline carvedilol Form II is formed by crystallizing carvedilolfrom the solvents listed in Table I. Carvedilol is crystallized byforming a solution of carvedilol heated to reach a clear solution,usually close to the solvent boiling temperature. The solution is thencooled to ambient temperature and the precipitate is filtered to yieldcarvedilol Form II.

TABLE I Solvent Ratio of Solvent (mL):Carvedilol (g) Methanol 11 Ethanolabs. 12 1-Propanol 14 Isopropanol 13 n-Butanol 11 Ethylene Glycol 13Ethyl-Acetate 10 Butyl Acetate 12 Isobutyl Methyl 12 KetoneDichloromethane 12 Dichloroethane 25 Acetonitile 50 Acetone 25

Example 5 Preparation of Crystalline Carvedilol Form II by Filtration at−20° C.

Crystalline carvedilol Form II is formed by crystallizing carvedilolfrom the solvents listed in Table II. Carvedilol is crystallized byforming a solution of carvedilol heated to about the solvent boilingtemperature. The solution is then cooled to −20° C., the precipitate isfiltered and dried to yield carvedilol Form II.

TABLE II Ratio of Solvent (ml): Solvent Carvedilol (g) Isoamylalcohol 50Toluene 53 Xylene 51

Example 6 Preparation of Crystalline Carvedilol Form II in SolventMixtures

Crystalline carvedilol Form II is formed by crystallizing carvedilolfrom the mixture of solvents listed in Table III. Carvedilol iscrystallized by forming a solution of carvedilol heated to form a clearsolution, usually close to the boiling temperature of the mixture ofsolvent. The solution is then cooled to ambient temperature andfiltered. The crystals are collected by filtration and dried to yieldcarvedilol Form II.

TABLE III Ratio Solvent (ml): Carvedilol (g) [Please Solvents ConfirmSolvent ratio Units] Acetone: 1:4.8 230 Cyclohexane Chloroform: 1:3 130Cyclohexane Dichloroethane: 1:2.5 142 cyclohexane Dichloromethane: 1:1.790 Cyclohexane Pyridine: 1:3.5 45 Cyclohexane Tetrahydrofurane: 1:2.5 53Cyclohexane Dioxane: 1:2.3 70 Cyclohexane Acetone:Hexane 1:2 235Chloroform: 1:1.5 87 hexane Dichloroethane: 1:1.2 89 HexaneDichloromethane: 1:1.6 90 hexane Tetrahydrofuran: 1:3 49 HexaneEthanol:Hexane 1:3.8 145

Example 7 Preparation of Crystalline Carvedilol Form III

Carvedilol (4 g) was dissolved in 45 mL of a mixture of 96% Ethanol and4% water by heating the mixture under stirring in a 55° C. water bath.The solution was cooled and left at room temperature without stirringfor about 14 hours, the crystals were filtered through a buchner funnel,rinsed twice with about 10 ml cold (4° C.) 96% ethanol, and dried in adesiccator at room temperature (connected to air pump) until constantweight to yield carvedilol Form III.

Example 8 Preparation of Crystalline Carvedilol Form III

Carvedilol (4 g) was dissolved in 195 mL mixture of water/methanol (in aratio 1:3 respectively) by heating the mixture under stirring in 55° C.water bath. The solution cooled to ambient temperature and left atambient temperature without stirring for about 15 hours, the crystalswere filtered through a buchner funnel and dried in a desiccator at roomtemperature (connected, to air pump) until constant weight to yieldcarvedilol Form III.

Example 9 Preparation of Crystalline Carvedilol Form III

Carvedilol (4 g) was dissolved in 39 mL pyridine by stirring at roomtemperature. 70 mL of water was then added dropwise untilcrystallization began. The solution was left at room temperature withoutstirring for about 80 hours, then the crystals were filtered through abuchner funnel and dried in a desiccator at room temperature (connectedto air pump) until constant weight to yield carvedilol Form III.

Example 10 Preparation of Crystalline Carvedilol Form III

Carvedilol (4 g) was dissolved in 76 mL dioxane at room temperature, and110 mL of water were added in portions of about 10 mL to the stirredsolution. The resulting solution was left at room temperature withoutstirring for about 15 h, then the crystalline precipitate which hadformed was filtered through a buchner funnel and dried in desiccator atroom temperature (connected to air pump) until constant weight to yieldCarvedilol Form III in a mixture with Carvedilol Form II.

Example 11 Preparation of Crystalline Carvedilol Form III

Carvedilol (4 g) was dissolved in 267 mL dioxane/water in the ratio1:1.4 respectively by heating the mixture under stirring at 55° C. waterbath. The resulting solution was left at room temperature withoutstirring for about 15 h then the crystals were filtered through abuchner funnel and dried in a desiccator (connected to air pump) untilconstant weight to yield Carvedilol Form III in a mixture withCarvedilol Form II.

Example 12 Preparation of Crystalline Carvedilol Form III

Carvedilol (4 g) was dissolved in 180 ml, Hexane/IPA in a ratio 1:1 byheating the mixture under stirring at 55° C. water bath. The solutionwas allowed to sit at room temperature without stirring for about 15 h,then the resulting crystals were filtered through a buchner funnel anddried in a desiccator (connected to air pump) at room temperature untilconstant weight to yield Carvedilol Form III.

Example 13 Process for Preparing Form III of Carvedilol

Carvedilol (40 g) was dissolved in 150 ml of ethanol and 40 ml water.The solution was heated with agitation to 60-70° C. until the solidmaterial was completely dissolved. The solution is then cooled withagitation to 10° C. over a period of 3 hours. After stirring thesuspension for an additional 2.75 hours, the product is filtered. PureCarvedilol Form III (35 g) was obtained.

Example 14 Preparation of Crystalline Carvedilol Form IV

Carvedilol (1 g) was dissolved in 35 mL methyl ethyl ketone by stirringat room temperature, and 202 mL cyclohexane was added dropwise. Thesolution was left at room temperature without stirring for about 15 h,then the resulting crystals were filtered through a buchner funnel anddried in a desiccator at room temperature (connected to air pump) untilconstant weight to yield carvedilol Form IV.

Example 15 Preparation of Crystalline Carvedilol Form V

Carvedilol (1 g) was dissolved in 70 mL methyl ethyl ketone by stirringat room temperature, and 138 mL hexane were added dropwise. The solutionwas left at room temperature without stirring for about 15 h, then theresulting crystals were filtered through a buchner funnel and dried in adesiccator at room temperature (connected to air pump) until constantweight to yield carvedilol Form V.

Example 16 Preparation of Crystalline Carvedilol Form V

Carvedilol (2 g) was dissolved in 45 mL methyl ethyl ketone by heatingthe mixture under stirring at 55° C. water bath, then the solution wascooled and left at room temperature without stirring for about 14 hours,the crystals were filtered through a buchner funnel and dried in adesiccator at room temperature (connected to air pump) until constantweight to yield carvedilol Form V.

1. Carvedilol HCl Hydrate.
 2. The carvedilol of claim 1 wherein thecarvedilol HCl hydrate is crystalline.
 3. The crystalline carvedilol ofclaim 2 characterized by an X-ray powder diffraction pattern havingpeaks at about 6.5±0.2, 10.2±0.2, 10.4±0.2, 15.8±0.2,16.4±0.2 and22.2±0.2 degrees two-theta.
 4. The crystalline carvedilol of claim 3,further characterized by an X-ray powder diffraction pattern havingpeaks at about 14.2±0.2, 14.7±0.2, 16.4±0.2, 17.7±0.2, 20.0±0.2,21.5±0.2, 21.9±0.2, 22.9±0.2, 25.2±0.2, 25.3±0.2, 27.2±0.2, 27.4±0.2,28.2±0.2, 28.6±0.2, 29.6±0.2 degrees two theta.
 5. The crystallinecarvedilol of claim 2 characterized by a water content of about 3.5% byweight.